SUMMARY. Most studies of Chronic Fatigue Syndrome (CFS) have been based
on patients recruited from primary or tertiary care settings. Patients
from such settings might not be typical of patients in the general
population and may not accurately reflect the heterogeneity among
individuals diagnosed with this condition. The current paper reviews four
community-based studies that examined subtypes of individuals with CFS.
Distinctions between subtype groups based on sociodemographics, illness
onset and duration, stressful precipitating events, symptom frequency,
and comorbidity characteristics are made with respect to outcome measures
of fatigue and symptom severity, functional ability, and psychiatric
comorbidity.

KEYWORDS. CFS definition, symptomatology, population studies

INTRODUCTION:
Chronic Fatigue Syndrome (CFS) is a highly heterogeneous condition,
affecting different people in different ways, and fluctuating in terms of
symptoms and severity during illness course (Anderson & Ferrans, 1997).
It can affect virtually every major system in the body; neurological,
immunological, hormonal, gastrointestinal and musculoskeletal problems
have been reported (Friedberg & Jason, 1998). One major challenge facing
CFS research is the issue of patient heterogeneity. Across studies,
individuals with CFS have been found to differ with respect to
characteristics such as gender, ethnicity, and socioeconomic status, mode
of illness onset and duration of illness, symptom severity, functional
disability, psychiatric comorbidity, and coping styles (Friedberg &
Jason, 1998). As a result of this heterogeneity, findings emerging from
studies in a number of areas are, at best, discrepant, and at worst,
contradictory, and the field has become highly polarized with respect to
issues involving etiology, diagnosis, epidemiology, and treatment.
Uncontrolled patient heterogeneity in empirical studies is one
consequence of ignoring this important issue of sub-classification. When
unique patient groups are unwittingly combined, any distinctions
pertaining to specific subtypes of CFS become blurred.

For years, investigators have noted many biological abnormalities among
patients with CFS, including over-activated immune systems (Landay,
Jessop, Lennette, & Levy, 1991), biochemical dysregulation in the 2-5A
synthetase/RNase L pathway (Suhadolnik et al., 1997), cardiac dysfunction
(Lerner, Lawrie, & Dworkin, 1993), EEG abnormalities (Donati, Fagioli,
Komaroff, & Duffy, 1994), abnormalities in cerebral white matter
(Natelson, Cohen, Brassloff, & Lee, 1993), decreases in blood flow in
certain areas of the brain (Schwartz et al., 1994), and autonomic nervous
system dysfunction (Freeman & Komaroff, 1997). However, there has been a
lack of consistency in such laboratory findings, which may be a function
of combining distinctive groups of patients into a large heterogeneous
group rather than analyzing them within subtypes.

Recent studies illustrate that sociodemographic variables can play an
important role in highlighting key distinctions between individuals with
CFS surrounding illness severity and functional disability. Several
studies have highlighted commonalities among individuals with CFS,
including greater likelihood of being female, Caucasian, and of higher
socioeconomic status (Reyes et al., 1997; Gunn, Connell, & Randall,
1993). However, community-based studies involving representative samples
of ethnically and socioeconomically diverse populations indicate that the
prevalence of CFS is actually higher for minority groups of Latinos and
African-Americans than for Caucasians (Jason, Richman et al., 1999), and
higher for individuals of lower socioeconomic status than for those of
higher socioeconomic status (Wessely, Chalder, Hirsch, Wallace, & Wright,
1997). CFS continues to be found to be more prevalent among women than
men (Jason, Richman et al., 1999), and there is some evidence to indicate
that there are gender-related differences in the impact of CFS as well as
in prevalence. Among a sample of individuals with CFS, women were found
to have a higher frequency of fibromyalgia, tender/enlarged lymph nodes,
and lower scores on the physical functioning subscale of the MOS, while
men had higher frequency of pharyngeal inflammation and a higher lifetime
prevalence of alcoholism (Buchwald, Pearlman, Kith, & Schmaling, 1994).
It is important for investigators to more frequently examine
sociodemographic subtype differences like these in patients with CFS.

Findings from many empirical investigations of CFS suggest that subtypes
of patients can be also distinguished with respect to the mode of illness
onset (whether gradual or sudden) (DeLuca, Johnson, Ellis, & Natelson,
1997; Reyes et al., 1999; Komaroff, 1988, 1994; Levine, 1997), the
presence of a stressful life event preceding or precipitating onset of
CFS (Ray, Jeffries, & Weir; 1995; Salit, 1997; Theorell, Blomkvist,
Lindh, & Evengard, 1999), and the duration of the illness. Reyes and
associates (1999), examined symptoms experienced at illness onset for
individuals with either sudden or gradual onset of CFS. Those with sudden
onset reported significantly more symptoms at onset than those with
gradual onset, and symptoms were more likely to be of infectious nature,
including fever, sore throat, chills, and tender lymph nodes. This is
consistent with other research (Komaroff, 1988, 1994) suggesting that
sudden onset of CFS may be indicative of viral or other infectious
illness. Some evidence indicates that individuals with CFS have
experienced a higher frequency of negative life events in the time
directly preceding the onset than matched controls ( Salit, 1997;
Theorell et al., 1999). With respect to duration of illness, some
researchers (Clark et al., 1995; Ray, Jeffries, & Weir, 1997) have
determined that persistent illness and poorer outcomes could be predicted
by longer duration of CFS symptoms. Wilson and associates (1994),
however, did not find duration of illness to be a predictor of outcome,
and Hill, Tiersky, Scavalla, and Natelson (1999) found that neither
duration of illness nor mode of onset predicted illness outcome. Clearly,
more research is needed to examine these important subtypes.

Findings suggest that patients with CFS can also be distinguished in
terms of symptom frequency and severity. In a US sample, Manu and
associates (1988) found a bimodal distribution of symptoms among 100
chronic fatigue patients, including 21 patients with 10-15 symptoms and
79 patients with 0-9 symptoms. In two follow-up studies of patients with
CFS, persistent symptoms and disability at the follow-up were associated
with having eight or more medically unexplained symptoms at initial
evaluation (Clark et al., 1995; Bombardier & Buchwald, 1995). A
comparison group of non-CFS chronic fatigue patients exhibited fewer
symptoms and higher functioning (Bombardier & Buchwald, 1995). It seems
apparent that patients with a higher number of symptoms are more
functionally impaired than those with fewer symptoms.

Many of the symptoms associated with CFS are also characteristic of
Fibromyalgia (FM). In the absence of definitive diagnostic markers or
laboratory tests to distinguish these conditions, clinical diagnosis is
largely based on self-report symptoms and behavioral criteria. Several
previous studies have suggested that CFS and FM have many similarities
(Buchwald, 1996; Goldenberg, 1988; Goldenberg, Simms, Geiger & Komaroff,
1990), although rates of comorbidity between CFS and FM are highly
disparate. Another subtype that would be useful to investigate in future
studies involves comparing those patients with only CFS versus those
patients with CFS and FM.

In addition to comorbidity of medical illnesses such as FM with CFS,
debate exists with respect to the issue of psychiatric comorbidity among
individuals with CFS, and the research community is polarized as to the
role of psychiatric illness in the etiology, course, and progress of CFS.
Some researchers ( Gold et al., 1990; Katon, Buchwald, Simon, Russo, &
Mease, 1991; Manu, Lane, and Matthews, 1988; Taerk, Toner, Salit,
Garfinkel, & Ozersky, 1987) have found psychiatric illness to play a
primary role in development and course of CFS, while others (Hickie,
Lloyd, Wakefield, & Parker, 1990; Yeomans & Conway, 1991; Stone et al.,
1994) have provided evidence against such findings. Comparing patients
with psychiatric comorbidity versus those without psychiatric comorbidity
involves another important area of subtyping for CFS research.

Findings from a community-based epidemiologic study of CFS have examined
several distinctive subtype groups of individuals with CFS, including
subtypes based on sociodemographic variables (Jason et al., 2000a),
variables related to illness onset and duration (Jason et al., 2000b),
symptom frequency (Jason et al., 2001a), and comorbidity with other
illness, including fibromyalgia and psychiatric illness (Jason et al.,
2001b). This article reviews and summarizes results of these studies, and
highlights the implications of subtype findings for future research.
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